Role of EXT1 and Glycosaminoglycans in the Early Stage of Filovirus Entry

Filoviruses, including both Ebola virus (EBOV) andMarburg virus (MARV), can infect humans and other animals, causing hem-orrhagic fever with a highmortality rate. Entry of these viruses into the host is mediated by a single filoviral glycoprotein (GP). GP is composed of two subunits: GP1, which is responsible for attachment and binding to receptor(s) on susceptible cells, and GP2, which mediates viral and cell membrane fusion. Although numerous host factors have been implicated in the entry process, the initial attachment receptor(s) has not been well defined. In this report, we demonstrate that exostosin 1 (EXT1), which is in-volved in biosynthesis of heparan sulfate (HS), plays a role in filovirus entry. Expression knockdown of EXT1 by small interfer-ing RNAs (siRNAs) impairs GP-mediated pseudoviral entry and that of infectious EBOV andMARV in tissue cultured cells. Fur-thermore, HS, heparin, and other related glycosaminoglycans (GAGs), to different extents, can bind to and block GP-mediated viral entry and that of infectious filoviruses. These results strongly suggest that HS and other related GAGs are attachment recep-tors that are utilized by filoviruses for entry and infection. These GAGsmay have therapeutic potential in treating EBOV- and MARV-infected patients. IMPORTANCE Infection by Ebola virus andMarburg virus can cause severe illness in humans, with a highmortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The ongoing 2014 outbreak inWest Africa underscores a lack o